Induction of RISK by HMG-CoA reductase inhibition affords cardioprotection after myocardial infarction

ObjectivesCoronary occlusion and revascularization leads to myocardial damage and heart function deterioration. Statins can regress atherosclerosis and modulate platelet function, but their effect on post-acute myocardial infarction (AMI) injury remains to be fully determined. We sought to examine whether rosuvastatin (R) exerts any effect on the RISK/apoptosis pathway when administered early after coronary reperfusion.MethodsPigs were fed 10 days a hypercholesterolemic diet before AMI induction and thereafter for 7 days randomly distributed to receive R or placebo (C) with the same diet. At sacrifice, hearts were sliced and alternatively collected for MI size and molecular analysis (gene and protein expression) in the peri-infarcted and remote myocardium. The RISK components (PKC, Erk2, and Akt/PKB) and downstream targets (HIF-1α and VEGF), and cell survival/apoptosis markers (Bcl-2, Bax, and Caspase-3) were analyzed. Annexin-V, Mito-Tracker staining, and inflammatory infiltration were also evaluated.ResultsR enhanced PKC, Erk2, Akt/PKB and its downstream effectors, and attenuated inflammation and cardiomyocyte apoptosis in the peri-infarcted zone (p < 0.05). No changes were detected in the remote myocardium. Infarct size was smaller in R than in C pigs (7% absolute reduction; 36% relative reduction; p < 0.05) and was associated with an absolute 12% recovery of LVEF (24% relative restoration; p < 0.05 vs. post-AMI).ConclusionsHMG-CoA inhibition early after reperfusion activates RISK kinases, reduces the extent of damaged myocardium, and improves heart function.